This episode reviews a perspective on the Global Parkinson’s Genetics Program (GP2), a coordinated international effort to expand Parkinson disease genetic discovery across underrepresented populations by combining large-scale genotyping, sequencing, capacity building, and open data sharing.
0:18Welcome to Base by Base, the papercast that brings genomics to you, wherever you are. Thanks for listening, and don't forget to follow and rate us in your podcast app. We are starting off our deep dive today with a number that should honestly give everyone pause.
0:31It's a big one. It really is. So between 1990 and 2021, the global prevalence of Parkinson's disease skyrocketed by 60.7%. Which is just a massive statistical jump. Massive. And the steepest climbs, they aren't happening in places like North America or Western Europe.
0:51They are actively occurring across low and middle income countries. Right, and that statistic really reframes our whole baseline understanding of this disease. I mean, for a long time, the public perception has basically been that this is an issue primarily for, you know, aging populations and high income nations.
1:06Yeah, like it's a wealthy country problem. Exactly. But in reality, it is a rapidly escalating global health crisis. We're seeing this surge driven by just a really complex mix of changing demographics, environmental factors, and, well, simply increasing lifespans worldwide.
1:22But here is the fundamental dilemma we face with all this. Even though Parkinson's is a global crisis affecting people across every single continent, almost all of our understanding of the underlying genetics comes from populations of northern European ancestry.
1:37It's incredibly skewed. It is entirely like trying to map the whole ocean by only studying a single bay. I mean, how can we possibly develop precision treatments for a global disease when our genetic map actively ignores the vast majority of the human population?
1:52We simply cannot. We just can't. Genetics dictates the foundational biological mechanisms of risk and disease. So if we are missing the genetic pieces from most of the world's populations, we are actively blinding ourselves to potential cures.
2:08We're operating with this fundamentally incomplete picture. Which obviously severely limits our ability to understand the disease's underlined biology, let alone figure out how to stop it at the cellular level.
2:18Exactly. It's like trying to put together a puzzle with half the pieces missing. Today, we celebrate the work of the global Parkinson's genetics program. or GP2, along with the aligning science across Parkinson's initiative and the Michael J. Fox Foundation, who have advanced her understanding of the genetic basis of Parkinson's disease on a global scale.
2:37And just to give you a sense of the scale of this effort. I mean, GP2 is a massive collaborative endeavor. We are talking about 275 distinct research groups. Wow. Yeah, operating in over 60 countries. They've really set out to build a truly global repository of genetic data, completely reshaping the foundation of how we study neurodegeneration across the world.
3:00Okay, let's unpack this. Why is Parkinson's so difficult to pin down biologically in the 1st place? Because from an outside perspective, you hear the word Parkinson's and you think of very specific visible motor symptoms.
3:11Well, historically, observing those exact symptoms is how it has been diagnosed in the clinic. It's defined by observing specific physical hallmarks, primarily what we call bradykinesia. is the slowness of movement, right?
3:21Yeah, a pronounced slowness of movement, along with muscle rigidity and resting tremors. And for decades, the medical consensus has operated on the assumption that these clinical symptoms correspond to a very specific neuropathological change deep in the brain.
3:37The Louis bodies. Exactly. Researchers point to the degeneration of the Negrustriattle pathway, which is basically the brain's main dopamine producing superhighway, and the buildup of those toxic protein clumps, the Louis bodies.
3:51So the clinical diagnosis relies entirely on what doctor sees in the exam room, operating on the assumption that the biological machinery failing inside the brain perfectly matches those outward signs.
4:01That has been the standard practice forever. But the biological reality is incredibly heterogeneous. I mean, you can have 2 patients with the exact same outward symptoms, but their disease behaves completely differently.
4:13Really? How so? Well, one patient might progress rapidly and develop severe cognitive impairment, while another experiences a much slower progression, focusing almost entirely on just the motor symptom.
4:24Okay, that makes sense And as our technology for looking into the living brain has evolved, we've realized that the visible clinical symptoms do not consistently align with the expected underlying biology.
4:36So if a clinical diagnosis isn't a reliable predictor of the actual biology, how are researchers supposed to find the right genetic targets? That's the big question. And that's where the biomarker shift really changes the game, right?
4:50Because researchers have recently developed a test called the alpha Senucleine seed amplification assay, or alpha SAA. Yes. This asset is just a brilliant piece of technology. It basically looks for the abnormal misfolding of the alpha senucleine protein, which is the main structural ingredient of those Louis bodies we just talked about.
5:09Right, the clumps. Right. And it detects this by leveraging the protein's own destructive behavior. It introduces a tiny sample from a patient into a controlled environment to see if any misfolded proteins act as a, well, like a seed.
5:23Forcing normal proteins to misfold and club together. Exactly. Amplifying the signal until we can actually detect it. The results of applying this assay to real patients are staggering, though. The data reveals that between 5 and 15% of people who have the classic clinical symptoms of Parkinson's actually test completely negative for these alpha synuclean aggregates.
5:45Which is wild. They have the outward tremors. They have the rigidity, but they fundamentally do not have Louis body disease in their brains. Wow. And the plot thickens considerably when we bring genetics back into the equation.
5:56Up to a third of people who carry mutations in a highly studied, high-risk Parkinson's gene called LRRK2 are also alpha SAA negative. Wait, up to a third. Up to a third. They carry the genetic risk factor, they exhibit the clinical symptoms, but they completely lack the classic protein buildup we've historically associated with the disease.
6:16So it basically means Parkinson's disease isn't one singular biological malfunction. It's more of a broad clinical umbrella term, covering potentially several distinct biological breakdowns. Exactly. And if we zoom out and look at the landscape of drug development, the implications are massive.
6:33Pharmaceutical companies are out there designing multimillion dollar drugs, specifically intended to clear out alpha cinucleine aggregates. Oh, I see where this is going. Yeah, if they test those drugs on a group of patients diagnosed purely by clinical symptoms, the trial is guaranteed to fail in the patients who don't actually have that specific underlying protein problem.
6:52Because you can't treat a protein aggregation problem. If the patient doesn't have that protein aggregation no matter how much their hand is shaking in the clinic. Bingo. This is the exact reason why a transition from a purely clinical definition to a strict biological definition of the disease is absolutely imperative.
7:10If we want precision medicine, We have to isolate precise biological targets. And genetics is obviously the map defining those targets. But the scientific community has a lot of catching up to do here.
7:22Over the last 30 years, researchers have isolated more than a dozen high risk or disease causing genes names like SNCA, PRKN, and VPS 35. Right, along with over 100 common genetic risk variants. Yeah, despite decades of work, all of this only explains about 30% of the disease's heritability.
7:41Yeah, that 30% figure is a glaring indicator of the massive knowledge gap we still face. And we have to remember that 30% is almost exclusively derived from studying northern European genomes. Which goes back to the ocean and the Bay analogy.
7:54Precisely. By expanding our search globally. We aren't just looking to fill in the missing 70% with more of the same data. We are actively hunting for entirely new biological mechanisms of disease that simply don't exist or, you know, are incredibly rare in European populations.
8:12Moving from the knowledge gap to the operational reality of actually fixing it. When research is going to underrepresented regions to collect DNA, how do they avoid helicopter science, just taking samples and giving nothing back?
8:25Because there is a long, unfortunate history of that in genetics. Researchers fly into a developing nation, draw blood, take the data back to a Western university, publish a high impact paper, and the local community never sees a single tangible benefit.
8:39You cannot build a global, sustainable scientific network on a foundation of extraction. GP2 recognize this from day one. To gather data from their target of 265,000 subjects ethically, they implemented a decentralized methodology focused on 4 core actionable areas.
8:58Okay, what's the 1st one? The 1st is global collaboration and capacity building. Which sounds great, but building a biorepository in a place like Lima, Peru, or Lagos, Nigeria, sounds fantastic on paper.
9:11Physical infrastructure is incredibly expensive to maintain long term. How does GP2 ensure these facilities don't just turn into abandoned warehouses once the initial grant money runs out? And that is the critical difference between funding a project and truly building capacity.
9:24GP 2 isn't just paying for the concrete in the freezers. They are deeply integrating these facilities with local health systems and academic institutions, ensuring that the physical samples and the capability to store, process, and ultimately utilize them for local grants remain under the control of the regions they come from.
9:41It shifts the power dynamic entirely. Okay, that makes a lot of sense. And the 2nd pillar they focus on is democratizing data, which addresses a huge bottleneck. Because having the physical samples is one thing, but analyzing genomic data requires massive, expensive computational power.
9:58Right. And to solve that, GP2 utilizes a central cloud-based platform where all the data is stored and harmonize, think of it like trying to assemble a 1000000 piece jigsaw puzzle where the pieces were originally cut by 60 different factories.
10:13Exactly. Centralizing the data ensures everyone is using the same interlocking dye cut. So the data actually fits together perfectly. But crucially, GP2 actually covers the computational costs for approved projects.
10:26Oh, wow. Yeah, so a brilliant researcher in a low-income country isn't locked out of the analysis simply because their university can't afford expensive cloud server time. They are literally paying the server bill so the science can happen anywhere.
10:39And that feeds perfectly into their 3rd pillar, growing next generation leaders. This goes beyond just hosting a few webinars, doesn't it? Oh, far beyond that. GP 2 has established a trainee network of over 250 members.
10:52They have formally funded 13 PhDs and 12 masters students globally, and they offer more than 70 online courses translated into up to 100 different languages. That is incredible. 100 languages. Yeah, heavily focused on bioinformatics.
11:07And what makes this sustainable is they're trained the trainer model? They run in person data analysis workshops in places like Mexico, Kyrgyzstan and Malaysia. Oh I see. They find the most talented individuals in those initial workshops and teach them how to teach the curriculum to others, creating this compounding effect of local scientific expertise.
11:25And that local expertise is immediately put to use through their 4th pillar, which is applying transformative genetic methods. They aren't just shipping outdated sequencing machines to these regions. They are applying state-of-the-art dense genotyping and whole genome sequencing at a massive scale.
11:42And to govern all of this across 275 groups, GP2 operates on a strict no surprises policy overseen by a project proposal working group. What does that mean in practice? Well, if a researcher wants to analyze data across cohorts, they didn't personally collect, they have to submit a detailed proposal.
11:59The working group verifies that the appropriate local GP 2 members are involved, that the research is equitable and that it includes a training component. So local involvement is a mandatory prerequisite, not just a polite afterthought.
12:13Exactly. With this massive ethical infrastructure firmly in place. Let's talk about the scientific dividends. As of their 10th data release, GP2 has generated and made available whole genome and dense genotype data from roughly 83,000 individuals.
12:29And the results are already shifting our understanding of the disease. One of the crowning achievements so far has been the identification of a completely novel risk factor in individuals of African ancestry.
12:39This is RS3115534G, right? That's the one, a specific non-coding genetic variant. Here's where it gets really interesting. Discovering this specific non-coding variant. Didn't just give us a new typo in the DNA.
12:52It revealed a whole new mechanical breakdown for the disease. It disrupts what is called an entronic branch point in a well-known Parkinson's gene called GBA1. Yeah, and to understand why that matters.
13:04You can think of an Entronic branch point, like a critical navigation waypoint in a genetic sentence. Our genes are full of usable instructions called Exxons, separated by filler segments called introns.
13:17Right, the filler. The branch point tells the cells machinery exactly where to cut out the filler and paste the usable instructions together to form a coherent protein. When that way point is disrupted by this specific variant, the machinery gets confused.
13:31Splices it wrong. Right. Right. It leads to mispllicing, basically a bad edit of the genetic film, which results in a significant reduction in the crucial protein that the GBA one gene is supposed to produce.
13:42So by looking at a new population, researchers discovered exactly how that specific typo breaks the cellular machinery. And because the broader scientific community already knows GBA1 is an important pathway, there are already clinical trials out there, testing drugs that target it.
13:56Exactly. By identifying this new variant, GP2 immediately revealed a whole new population of patients, individuals of African descent who are biologically eligible for these GBA one-based clinical trials.
14:08Because previously, these patients might have been completely excluded, since they didn't carry the specific European centric mutations the trials were originally screening for. Right. It is the ultimate proof of concept for why diversity and genomic sequencing matters.
14:22It actively opens doors to therapies for people who were previously invisible to the research community. That's amazing. It also perfectly illustrates a key concept in genetics called pleomorphic whisk loci.
14:35We often conceptualize disease genes as a simple on off switch. You either have the mutation and get the disease or you don't. But in reality, genes like GBA1 or LRK2 exist on a broad continuum of risk.
14:51Meaning they contain multiple different variants that can come for widely varying levels of danger. Exactly. Some rare variants within these genes are highly penetrant, meaning if you carry the variant, you are almost certainly going to develop the disease.
15:02Other variants might confer a moderate risk, perhaps making YouTube 5 times more likely to develop Parkinson's. And some are just loo risk. Yeah, common variants that only bump up your statistical risk by a tiny fraction of a person.
15:15See, if a listener hears that a specific genetic variant only increases their disease risk by 2%, it's really easy to assume that the gene itself must not be very important for drug development. But the magnitude of the risk from a specific variant doesn't necessarily dictate the importance of the biological pathway, does it?
15:33No, and that is a very common logical fallacy in genomics. The effect size of the variant only tells us how much that specific DNA change alters the proteins function. The biological pathway itself might be absolutely central to the disease process.
15:49The true value of finding these genetic variants, even the ones that confer very low risk, is that they act like a giant neon sign pointing researchers toward the exact biological pathway that needs to be therapeutically targeted.
16:02That makes sense. Statistically, drugs that are supported by unequivocal human genetic evidence are two to three times more likely to succeed in clinical development. So what does this all mean for a listener who might be worried about their own risk?
16:15Let's follow that neon sign from risk predictions straight to mechanism. Let's look at another variant GP 2 has investigated. Located in a gene called TMM 175. Finding this variant wasn't just about giving people a polygenic risk score to worry about, it revealed a specific underlying network.
16:33TMM 175 is a fascinating example. This gene regulates a potassium channel located inside lysosomes. And lysosomes are like the recycling centers of our cells, right? Or the stomachs of our cells, yeah.
16:45They require a highly specific acidic environment to melt down and clear out cellular trash, including abnormal proteins like alpha sinucleine. And the potassium channel is responsible for regulating that acidic environment.
16:58Correct. So when the TM 175 gene is varied and the potassium channel function is impaired, the acidic balance inside the lysosome is totally thrown off. So the recycling center stops working efficiently.
17:10The cellular trash builds up, and that directly affects how the cell clears out alpha synucleen. It connects the abstract genetic code straight back to the physical protein buildup. actually see in the brain.
17:21Once researchers know the underlying network is lysosomal function, they can start designing drugs that specifically target that potassium channel to restore the acidic balance. Exactly, to actually stop the disease process, rather than just treating a tremor after the neurological damage is already done.
17:38Operating a research network capable of making these kinds of discoveries across 60 countries for 5 years requires navigating immense logistical hurdles. What are the big lessons GP 2 has learned here?
17:51One of the biggest is the absolute necessity of flexible funding. Because they are funded by the ASAP initiative through the Michael J. Fox Foundation, they aren't tied to the rigid multi-year structure of a standard government grant.
18:04Which gives them agility. Right. If a new sequencing technology emerges or a sudden legal hurdle appears in a specific country, they have the operational agility to course correct immediately. I imagine the legal complexities of moving human genomic data across international borders are staggering.
18:21I mean, how does GP2 navigate the concept of data sovereignty, where countries rightfully view their citizens' genetic data as a protected national asset? It requires massive operational investment, you are dealing with the GDPR in Europe, the LGPD in Brazil, Popia, and South Africa, and dozens of other distinct national privacy frameworks.
18:42That sounds like a compliance nightmare. It is complex. GP 2 has had to work site by site to establish collaborative data sharing solutions. Sometimes this means federated analysis. Which means the data physically stays within the host country's borders.
18:56Exactly. And the researchers send their analytical code to the data rather than moving the data to the researchers. Looking at their trajectory, GP2 is rapidly expanding. They anticipate identifying over 50 new global and ancestry specific risk variants in the near future.
19:10And furthermore, they're actively exploring how to take these discoveries out of the database and return the genetic results directly to the patients across different regions, partnering with clinical testing initiatives like PD generation.
19:21Returning those results as the ultimate goal. As we isolate more actionable genetic targets, like the GBA one variant in African populations, genetic testing transitions from a purely research focused endeavor into a critical clinical tool.
19:35Because it matches people to treatments. It becomes the exact mechanism for matching individual patients to the right critical trials, regardless of where they live in the world. To truly cure a complex global disease like Parkinson's, our scientific baselines simply must reflect the entire globe.
19:53By building sustainable local research capacity and democratizing access to massive genetic data sets, GP2 is forcefully moving the scientific community away from incomplete Eurocentric data toward true precision medicine for everyone.
20:07What does this mean for the future of treating other complex global diseases, and could this collaborative capacity building model become the new gold standard for all genetic research? If we want to actually solve global health crises, it absolutely has to become the standard.
20:21There's no other way forward. This episode was based on an open access article under the CCBY 4.0 license. You can find a direct link to the paper and a license in our episode description. If you enjoyed this, follow or subscribe in your podcast app and leave a 5 star rating.
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